The innate and adaptive immune systems represent our two arms of defense against infection and cancer. Natural killer (NK) cells are a central component of innate immunity, recognizing infected cells, stressed cells and tumor cells via specific nonpolymorphic receptors. As the critical presenters of antigen to naive T cells, dendritic cells (DCs) are the critical initiators of adaptive immunity. Coordination of immune responses requires efficient communication between innate and adaptive immunity. Recently, we discovered a unique hybrid cell type that expresses both NK molecules (activating and inhibitory) and DC molecules, termed NKDC. Murine NKDCs are related to, but distinct from classic plasmacytoid DC (PDCs). Upon activation with CpG oligonucleotide ligands for toll-like receptor (TLR)-9, NKDC become transiently activated to kill target cells. The killing is, at least in part, NKG2D-dependent. Their NK activity subsequently diminishes associated with loss of NKG2D and its adaptor, DAP-12. As NK activity is lost, DC-like antigen presenting activity is gained, associated with upregulation of surface MHC class II and costimulatory molecules. In vivo, splenic NKDCs preferentially display NK activity while lymph node NKDCs preferentially display ARC activity. By virtue of their capacity to mediate natural killing activity, followed by antigen presenting activity, NKDC may represent a direct link between innate and adaptive immunity. We propose to characterize the development and functions of this cell type in detail. The following specific aims will be pursued. Specific Aim #1: Define the developmental biology of NKDC relative to NK cells and classic DC.Specific Aim #2: Define the activation, recognition and effector molecules involved in NKDC killing. Specific Aim #3: Define the capacity of NKDC to process and present antigens to T cells. Specific Aim #4: Define the role of NKDC in response to tumors. [unreadable] [unreadable]